Toxicity of Pesticide Mixtures

Pesticides are often applied in mixtures. Mixtures of herbicides, fungicides, and pesticides are applied to corn, cotton, lettuce, and fruit crops, 6l As a result, pesticides are widely present in the environment as mixtures. This point is underscored by the finding that more than 50% of all streams tested in the United States contained five or more pesticides. 2l 

The toxic effects of some pesticide mixtures are additive, particularly when their toxic mechanisms are identical. The additive effects of the organophosphates chlorpyrifos and diazanon were demonstrated in one study. T Another study found the s-triazine herbicides atrazine and cyanazine to show additive toxic effects. Not all mixtures of similar pesticides produce additive effects, however. In one study, mixtures of five organophos-phate pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) were shown to produce greater than additive effects when administered to laboratory animals. Another article discusses nonsimple additive effects of pyrethroid mixtures. Despite the similarities in their chemical structure, pyrethroids act on multiple sites, and mixtures of these produce different toxic effects. 10  

Amphibian endocrine disruption is of special interest to humans. The estrogen found in the painted turtle is identical to that found circulating in the human bloodstream and the endocrine disruptors that threaten wildlife populations have also been shown to be jeopardizing human reproductionAccordingly, animal studies on endocrine disrupting properties of toxic chemicals are relevant to understanding human responses to these chemicals. Pesticide mixtures have been shown to be powerful endocrine disruptors in numerous other animal studiesJ16 Illustrative examples follow. 

The chlorinated pesticides DDT and chlordecone are known to generate deleterious reproductive effects. In a bioassay of these and other chlorinated pesticides on cultured human breast estrogen-sensitive MCF7 cells, it was shown that dieldrin, toxaphene, and endosulfan have estrogenic properties comparable to those of DDT and chlordecone. When tested together, the mixture of the three pesticides induced estrogenic responses 

The urine of randomly selected men in agricultural environments of reproductive age was analyzed for parent compounds and metabolites of pesticides and was compared with sperm concentration. The results showed that those exposed to mixtures of organophosphates and pyrethroids had lower sperm concentrations, and that sperm concentration was related to the exposure levels of the two pesticide categories, 19  

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Belden JB, Gilliom RJ, Lydy MJ. 2007. How well can we predict the toxicity of pesticide mixtures to aquatic life. Integrated Environ Assess Manage 3 362-372. 

In a study using a human neuroblastoma cell line, mixtures of three different organophosphates (azinphos-methyl, diazanon, and dimethoate), and mixtures of an organic phosphate (pirimiphos-methyl) and a benzim-idizole fungicide (benomyl) showed greater toxicity toward protein synthesis than the individual pesticides. I21 The authors of the study concluded that it is not feasible to predict the toxicities of pesticide mixtures on the basis of the toxicities of the single components. 

Although there is nu doubt (hut humans are exposed to low doses of mixtures of pesticides (Caslorina e( at, 2003 Duggan et ai, 2003 Fenskc et al. 2002 Sanchez-Pena et ai, 2004), the question is whether mixtures are more toxic than the sum of the toxicity for each pesticide alone. In the literature describing the toxicity of mixtures of organophosphorus (OP) or carbamate (CM) pesticides, concern is expressed that exposure to mixtures of pesticides may be much more toxic than the toxicity of the individual pesticides. This concern about potentiated toxicity is all the more worrisome because data are lacking on the toxicity of pesticide mixtures, whether OP or CM, at less than lethal dosages. There is such scarcity of data, and the data arc so disparate, that a science-ba.scd conclusion on the toxicity of OP or CM pesticide mixtures is not possible,... 

Macck, K. J. (1975). Acute toxicity of pesticide mixtures to blucgills. Bull. Environ. Contam. Toxical 14,648-652. 

Belden et al. (2007) used a 3-step approach to evaluate the relative toxicity and the occurrence pattern of pesticide mixtures in streams draining agricultural watersheds. First, a landscape of interest was identified as the corn-soybean crop setting in the United States. Second, the relative toxicity of mixtures was compared... 

Belden JB, Gilliom RS, Martin JD, Lydy MJ. 2007. Relative toxicity and occurrence patterns of pesticide mixtures in streams draining agricultural watersheds dominated by corn and soybean production. Int Environ Assess Manag 3 90-100. 

Murty A. 1986. Toxicity of pesticides to fish joint action of pesticide mixtures. Boca Raton (FL) CRC Press. 

Heindel JJ, Chapin RE, Gulati DK, et al. (1994) Assessment of the reproductive and developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater. Fundamental and Applied Toxicology 22 605-621. 

Biotransformation plays a significant role in species differences in susceptibility with many resistant species capable of pesticide detoxification, whereas susceptible species tend to bioactivate compounds to more reactive intermediates which may be more toxic. Environmental factors such as salinity and co-exposure to environmental hormones may also significantly affect biotransformation and potential toxicity of pesticides in fish. Clearly, preliminary studies with chemical mixtures have demonstrated a role for biotransformation in subsequent synergistic and antagonistic whole animal endpoints. Further work is necessary in this area as concomitant exposure represents a more realistic setting of xenobiotic exposure to fish since many pesticides are used in combination or may occur in waterways at the same time of the year. 

Very few investigators have ventured into the realm of mixture experiments during the past 40 years. These types of studies can be complicated and time-consuming. The overall design of these studies i,s usually one of (wo types those that determine the toxicity of a given mixture or those that determine if the interaction of two or more OP or CM pesticides is synergistic (i.e., if the toxicity of a mixture Ls more toxic than the sum of the toxicity of the individual pesticides that make up the mixture). 

Patel Y, Kushwah HS, Kushwah A, et al. 1998b. Effect of chronic pesticides mixture toxicity on some enzymes in rats. Indian Vet J 75 698-700. 

Due to the low volatility of cyromazine and the use of water-soluble bags for packaging the Trigard formulation, the main routes of exposure were expected to be from direct contact with the product or spray mixture on contaminated surfaces. Previous experience with pesticides worker exposure studies indicated that exposure from vapors or spray mist would be a minor factor. This can easily be confirmed by the PHED or similar published sources however, the extent of exposure from inhaling the product as dust is less well known. This route of exposure was also assumed to be minor, particularly with the use of water-soluble bag packaging. Given the low mammalian toxicity of cyromazine, the operators did not wear respiratory protection. 

Both Congress and EPA have a number of studies and efforts underway which may ultimately impact disposal of pesticide waste. Among these are reevaluation of the small generator exclusion limit, expansion of Extraction Procedure toxicity characteristic to include additional organic chemicals, revamping of Section 261. 33 (commercial chemical products which are hazardous waste when discarded or intended to be discarded) to both bring mixtures of active ingredients under the definition and also to establish concentration thresholds for the wastes, and a prohibition on land disposal of certain wastes. At this time I would like to briefly touch on each of these areas. 

The evaluation assumes that the hazard and possible risk of the defined (top-ten) mixture of chemicals is representative for the hazard and risk of the entire complex mixture. For some mixtures that are relatively easily available (e.g., combustion fumes, food products, pesticide mixtures), this assumption could be validated by comparing the toxicity of the top-ten mixture with the toxicity of the original complex mixture in short-term test. 

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